Clinical characteristics of T790M-positive lung adenocarcinoma after resistance to epidermal growth factor receptor-tyrosine kinase inhibitors with an emphasis on brain metastasis and survival

Joo, Jin Woo,Hong, Min Hee,Shim, Hyo Sup Elsevier 2018 Lung cancer Vol.121 No.-

<P><B>Abstract</B></P> <P><B>Objectives</B></P> <P>We aimed to investigate the clinical characteristics of lung adenocarcinomas with acquired <I>EGFR</I> T790M mutation focusing on brain metastasis and survival.</P> <P><B>Materials and methods</B></P> <P>Our study included patients who had lung adenocarcinoma harboring <I>EGFR</I> mutation at 1st biopsy and then underwent 2nd biopsy after resistance to first- or second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Statistical analyses were performed to examine the associations between clinicopathologic features of lung adenocarcinoma and presence of acquired T790M mutation.</P> <P><B>Results</B></P> <P>A total of 111 patients were identified. Of these, 58 patients (52.3%) had acquired T790M mutations. Osimertinib was used in 29 patients (26.1%) after resistance to first- or second-generation TKIs. The T790M mutation was more frequently found in patients with exon 19 deletion than in those with L858R mutations (p = .026) and in patients who had longer treatment duration with EGFR-TKI (p = .0398). Multivariate analysis revealed that exon 19 deletion (p = .003) were independently associated with T790M mutation. Patients with acquired T790M mutation showed a longer progression-free survival. In addition, patients who had T790M mutation or who received osimertinib treatment had a longer overall and post-progression survival than patients who did not. Brain metastasis-free survival was also longer in the T790M-positive group or osimertinib-treated group among patients who had no brain metastasis at the time of diagnosis. Osimertinib treatment was independently associated with longer overall, post-progression, and brain metastasis-free survival.</P> <P><B>Conclusion</B></P> <P>The status of acquired T790M mutation was correlated with exon 19 deletion and longer progression-free survival to first- or second-generation EGFR-TKIs. A third-generation EGFR-TKI, osimertinib, was strongly associated with brain metastasis-free survival as well as other survival indicators in patients with <I>EGFR</I>-mutant lung adenocarcinoma.</P> <P><B>Highlights</B></P> <P> <UL> <LI> T790M mutation is common in tumors harboring <I>EGFR</I> exon 19 deletion compared to L858R. </LI> <LI> Patients who had a T790M mutation and received osimertinib treatment had the best prognosis. </LI> <LI> Treatment with osimertinib is associated with prolonged brain metastasis-free survival. </LI> </UL> </P>

The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma

Yen-Hsiang Huang,Kuo-Hsuan Hsu,Jeng-Sen Tseng,Kun-Chieh Chen,Chia-Hung Hsu,Kang-Yi Su,Jeremy J. W. Chen,Huei-Wen Chen,Sung-Liang Yu,Tsung-Ying Yang,Gee-Chen Chang 대한암학회 2018 Cancer Research and Treatment Vol.50 No.4

Purpose The main objective of this study was to investigate the relationship among the clinical characteristics and the frequency of T790M mutation in advanced epidermal growth factor receptor (EGFR)mutant lung adenocarcinoma patients with acquired resistance after firstline EGFRtyrosine kinase inhibitor (TKI) treatment. Materials and Methods We enrolled EGFR-mutant stage IIIB-IV lung adenocarcinoma patients, who had progressed to prior EGFR-TKI therapy, and evaluated their rebiopsy EGFRmutation status. Results A total of 205 patients were enrolled for analysis. The overall T790M mutation rate of rebiopsy was 46.3%. The T790M mutation rates among patients with exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 55.0%, 37.3%, and 27.3%, respectively. Baseline exon 19 deletion was associated with a significantly higher frequency of T790M mutation (adjusted odds ratio, 2.14; 95% confidence interval [CI], 1.20 to 3.83; p=0.010). In the exon 19 deletion subgroup, there was a greater prevalence of T790M mutation than other exon 19 deletion subtypes in patients with the Del E746-A750 mutation (61.6% vs. 40.6%; odds ratio, 2.35; 95% CI, 1.01 to 5.49; p=0.049). The progression- free survival (PFS) of first-line TKI treatment > 11 months was also associated with a higher T790M mutation rate (54.1% vs. 39.3%; adjusted odds ratio, 1.82; 95% CI, 1.02 to 3.25; p=0.044). Patients who underwent rebiopsy at metastatic sites had more chance to harbor T790M mutation (52.6% vs. 33.8%; adjusted odds ratio, 1.97; 95% CI, 1.06 to 3.67; p=0.032). Conclusion PFS of first-line EGFR-TKI, rebiopsy site, EGFR exon 19 deletion and its subtype Del E746- A750 mutation are associated with the frequency of T790M mutation.

Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non–Small Cell Lung Cancer

이채린,김미소,김동완,김태민,김소연,임선화,전윤경,김범석,구자록,허대석 대한암학회 2022 Cancer Research and Treatment Vol.54 No.1

Purpose Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non–small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs. Materials and Methods We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening. Results In cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs. Conclusion Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.

Synthesis and biological evaluation of anilide derivatives as epidermal growth factor receptor L858R / T790M and L858R / T790M / C797S inhibitors

Kim Soo Lim,Yang Yo‐Sep,Lee Sujin,Kim Nam‐Jung 대한화학회 2022 Bulletin of the Korean Chemical Society Vol.43 No.8

Development of a mutant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor is important for the treatment of various cancers. Thirdgeneration EGFR tyrosine kinase inhibitors (TKIs) have been clinically used by targeting T790M specifically but are recently known to induce T790M/C797S mutation after the treatment. Therefore, there is an unmet need to develop novel kinase inhibitors targeting the mutant EGFRs. Here, we designed and synthesized 16 analogs by hybridizing EAI045 (1) and 30 ,40,50-trihydroxyflavone (2) and identified 9a, 9b, and 20b as EGFR L858R/T790M/C797S mutant inhibitors. In addition, we found that 10a and 10b can inhibit both L858R/T790M and L858R/T790M/C797S. Molecular docking study on a plausible binding mode of the compounds is also provided.

Differential MicroRNA Expression between EGFR T790M and L858R Mutated Lung Cancer

김지연,이우정,박하영,김아롱,신동훈,이창훈 대한병리학회 2018 Journal of Pathology and Translational Medicine Vol.52 No.5

Background: MicroRNAs (miRNAs) are short, non-coding RNAs that mediate post-transcriptional gene regulation. They are commonly deregulated in human malignancies, including non-small cell lung cancer (NSCLC). The aim of this study is to investigate miRNA expression in T790M-mutated NSCLC resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Methods: Six cases of resected NSCLC harboring the T790M mutation were examined. We performed miRNA time polymerase chain reaction (PCR) array profiling using EGFR T790M-mutated NSCLC and L858R-mutated NSCLC. Once identified, miRNAs that were differentially expressed between the two groups were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Results: miRNA PCR array profiling revealed three up-regulated miRNAs whose expression levels were altered 4.0-fold or more in the EGFR T790M mutation group than in the L858R group: miR-1 (fold change, 4.384), miR-196a (fold change, 4.138), and miR-124 (fold change, 4.132). The three differentially expressed miRNAs were validated by qRT-PCR, and they were found to be overexpressed in the T790M group relative to L858R group. In particular, expression levels of miR-1 and miR-124 were significantly higher in the T790M group (p-value of miR-1 = .004, miR-124 = .007, miR-196a = .096). Conclusions: MiR-1, miR-124, and miR-196a are overexpressed in EGFR T790M mutated NSCLC.

Early emergence of <i>de novo EGFR</i> T790M gatekeeper mutations during erlotinib treatment in PC9 non-small cell lung cancer cells

Kim, Sujin,Park, Angela KJ.,Cho, Jeonghee Elsevier 2018 Biochemical and biophysical research communication Vol.503 No.2

<P><B>Abstract</B></P> <P>The emergence of the T790M gatekeeper mutation in the <I>Epidermal Growth Factor Receptor</I> (<I>EGFR</I>) gene is an important mechanism that can lead to the acquired resistance to EGFR-targeted tyrosine kinase inhibitors such as erlotinib or gefitinib. These drugs have been used in treating a subset of non-small cell lung cancer (NSCLC) patients harboring <I>EGFR</I> activating mutations. Here we investigated the paths leading to the acquisition of the T790M mutation by establishing an erlotinib resistant PC9 cell model harboring ectopically introduced <I>EGFR</I> cDNA. We detected the emergence of T790M mutation within the <I>EGFR</I> cDNA in a subset of erlotinib resistant PC9 cell models through Sanger sequencing and droplet digital PCR-based methods, demonstrating that T790M mutation can emerge via <I>de novo</I> events following treatment with erlotinib. In addition, we show that the <I>de novo</I> T790M bearing erlotinib resistant PC9 cells are sensitive to the 3rd generation EGFR-targeted drug, WZ4002. Furthermore, GFP-based competition cell proliferation assays reveal that PC9 cells ectopically expressing EGFR mutant become more rapidly resistant to erlotinib than parental PC9 cells through the acquisition of the T790M mutation. Taken together, we believe that our findings expand upon the previous notion of evolutionary paths of T790M development, providing an important clue to designing a therapeutic strategy to overcome drug resistance.</P>

Safety, tolerability, and anti-tumor activity of olmutinib in non-small cell lung cancer with T790M mutation: A single arm, open label, phase 1/2 trial

Kim, Dong-Wan,Lee, Dae Ho,Han, Ji-Youn,Lee, Jongseok,Cho, Byoung Chul,Kang, Jin Hyoung,Lee, Ki Hyeong,Cho, Eun Kyung,Kim, Jin-Soo,Min, Young Joo,Cho, Jae Yong,An, Ho Jung,Kim, Hoon-Gu,Lee, Kyung Hee,K Elsevier 2019 Lung cancer Vol.135 No.-

<P><B>Abstract</B></P> <P><B>Objectives</B></P> <P>The aim of this phase 1/2 study was to evaluate the safety, tolerability, pharmacokinetics and antitumor activity of olmutinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who had failed ≥ 1 previous line of EGFR-tyrosine kinase inhibitor (TKI) therapy.</P> <P><B>Materials and methods</B></P> <P>Phase 1 consisted of dose-escalation and four dose-expansion parts (1: olmutinib 300 mg once daily; 2A: 800 mg once daily [<I>EGFR</I> T790 M mutation-positive patients]; 2B: 500 mg twice daily [<I>EGFR</I> T790 M mutation-positive]; 3: 800 mg once daily [<I>EGFR</I> T790 M mutation-negative]). In phase 2, <I>EGFR</I> T790 M mutation-positive patients received olmutinib 800 mg once daily. Data from expansion part 2A and phase 2 were integrated (`pooled phase 2′). Each olmutinib cycle was 21 days. Outcomes included: tumor response, treatment-emergent adverse events (TEAEs), pharmacokinetic parameters.</P> <P><B>Results</B></P> <P>Overall, 272 patients received at least one olmutinib dose: dose-escalation (n = 66), expansion parts (n = 165), phase 2 (n = 41). In pooled phase 2, the overall objective response rate, confirmed by independent review, was 55.1% (38/69 evaluable patients; 95% CI, 42.6–67.1). All responses were partial responses; 23 patients had stable disease. Estimated median progression-free survival was 6.9 (95% CI, 5.6–9.7) months; estimated median overall survival was not reached. The most frequent treatment-related AEs were diarrhea (59.2% of patients), pruritus (42.1%), rash (40.8%), and nausea (39.5%).</P> <P><B>Conclusion</B></P> <P>Olmutinib showed effective clinical activity with a manageable safety profile, indicating therapeutic potential for T790M-positive NSCLC patients who have failed ≥ 1 previous line of EGFR-TKI therapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Olmutinib showed effective clinical activity. </LI> <LI> The safety profile of olmutinib was manageable. </LI> <LI> Olmutinib showed potential in T790M-positive NSCLC after failing ≥1 prior EGFR-TKI. </LI> </UL> </P>

Predictive factors of osimertinib as salvage treatment for metastatic EGFR T790M positive lung adenocarcinoma

( Ji Young Park ),( Seung Hun Jang ),( Hwan Il Kim ),( Joo-hee Kim ),( Sunghoon Park ),( Yong Il Hwang ),( Ki- Suck Jung ),( Jinwon Seo ) 대한결핵 및 호흡기학회 2019 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.127 No.0

Background: EGFR T790M mutation is a robust biomarker for the efficacy of osimertinib. But its clinical efficacy is very limited in a part of patients with non-small cell lung cancer harboring EGFR T790M mutation, suggesting primary resistance. The purpose of this study was to discover clinical predictive factors for the efficacy of osimertinib. Methods: This retrospective study analyzed patients with stage IV, EGFR T790M positive lung adenocarcinoma given osimertinib as salvage treatment. Various baseline clinical factors were investigated according to favorable or unfavorable osimertinib efficacy group. Unfavorable efficacy (primary resistant) group was defined as progression- free survival (PFS) < 6 months with osimertinib. Results: Thirty patients were eligible for this analysis (19 of favorable and 11 of unfavorable efficacy group). PFS of favorable and unfavorable efficacy group with osimertinib were 9.9 months (95% CI 9.5- 10.3) and 3.3 months (95% CI 2.4-4.2), respectively (p<0.001). Response rate of osimertinib was 89.5% vs. 18.2% (p<0.001). The cases with age at the time of lung cancer diagnosis ≥ 60 years, baseline (before starting osimertinib) Neutrophil to Lymphocyte Ratio (NLR) ≤ 3.5, pre-osimertinib treatment with first-generation EGFR-TKI (gefintinib or erlotinib) rather than second-generation EGFR-TKI (afatinib) were more frequent in the favorable efficacy group (p=0.058, 0.058, and 0.088, respectively, chi-square test). Age at the time of lung cancer diagnosis, ECOG performance, baseline NLR, pre-osimertinib EGFR-TKI generation, and PFS with previous EGFR-TKI were revealed as potential predictive factors through Kaplan- Meier PFS estimation. Finally, Cox proportional hazard regression analysis confirmed age at the time of lung cancer diagnosis ≥ 60 years (HR 0.292, 95% CI 0.104-0.819, p=0.019) and baseline NLR ≤ 3.5 (HR 0.238, 95% CI 0.083-0.677, p=0.007) were good predictive factors for the efficacy of osimertinib. Conclusion: Relatively old age and low neutrophilic inflammation were associated with favorable efficacy of osimertinib.

A Phase II Trial of Osimertinib in the Second-Line Treatment of Non-small Cell Lung Cancer with the EGFR T790M Mutation, Detected from Circulating Tumor DNA: LiquidLung-O-Cohort 2

박철규,조현주,최유덕,오인재,김영철 대한암학회 2019 Cancer Research and Treatment Vol.51 No.2

Purpose Administering the best treatment after failure of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy requires knowledge of resistance status. In this trial, treatment efficacy of osimertinib was assessed in patients with non-small cell lung carcinoma (NSCLC) harboring the T790M resistance mutation, detected from circulating tumor DNA (ctDNA) with unknown tumor mutation status. Materials and Methods To extract ctDNA from plasma, 15 mL of peripheral blood was withdrawn and centrifuged immediately before storage. Cobas ver. 2 and PANA Mutyper were used for ctDNA genotyping. Patients with T790M, detected from ctDNA, were enrolled and they received a oncedaily administration of osimertinib 80 mg. The primary endpoint was objective response rate (ORR), and secondary endpoints were ctDNA test sensitivity, progression-free survival (PFS), duration of response (DoR), and safety. Results Eighty patients with acquired resistance to prior EGFR-TKI therapies were screened. ctDNA of 21 patients showed T790M positivity, and 19 patients were enrolled. In the responseevaluable population (n=15), ORR was 66.7% (10/15). Median PFS was 8.3 months (95% confidence interval [CI], 7.9 to 8.7) and median DoR was 6.8 months (95% CI, 5.3 to 8.3) in the intent-to-treat population (n=19). No subject experienced drug-related adverse event of grades  3 or required dose reduction. The sensitivity of the ctDNA tests was 56.8% using both methods and 45.9% with either method from the estimated T790M-positive cases. Conclusion Osimertinib has favorable efficacy in patients with NSCLC harboring T790M, detected from ctDNA with unknown tumor mutation status, in whom disease had progressed during prior EGFR-TKI therapy.

F-148 Feasibility and alternative approaches of rebiopsy in patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors

김희정,이종식,김인애,허재영,김순종,유광하,이계영 대한결핵 및 호흡기학회 2017 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.124 No.-

We aimed to investigate the feasibility of performing tumor rebiopsy in NSCLC patients who developed acquired resistance to EGFR-TKIs in a real-world setting. From October 2014 to December 2016 we enrolled patients who had disease progression after previous treatment with an EGFR-TKIs and underwent rebiopsy and/ or liquid biopsy including BAL and plasma sampling. DNA extracted from extracellular vesicles in BAL fluid and plasma was analyzed for EGFR mutation. We retrospectively reviewed patient characteristics, types of rebiopsy procedure, and responses to third generation EGFR TKIs. Thirty-one patients experienced progression to EGFR-TKIs. Rebiopsy was not possible in 7 patients and no tumor was provided in two cases. Out of 24 patients who performed rebiopsy, 22 patients were pathologically diagnosed with adenocarcinoma, though 5 patients have conducted rebiopsy two (n=4) or three times (n=1). T790M mutations were identified in 12 of the 22 patients whose tissues were available for EGFR mutation analysis. Among the patients who did not perform rebiopsy or who were not identified T790M mutation in tissue, 8 more T790M mutations were additionally found from BAL fluid (n=5) and plasma (n=3) respectively. A total of 16 out of the 20 patients with T790M mutations were treated with 3rd generation EGFR-TKIs and whose disease control rate was 76.5%. Liquid biopsy using EV DNA could significantly be alternative methods in case it is hard to obtain sufficient tissues for EGFR mutation analysis from the patients with NSCLC who need rebiopsy.